Oncogenic Signaling Pathways and Pathway-Based Therapeutic Biomarkers in Lymphoid Malignancies

Abstract

Lymphoma is characterized by heterogeneous biology, pathologic features, and clinical outcome. This has been proven by accumulating pathologic and molecular evidence attributed to underlying aberrant alterations at genetic, epigenetic, transcriptional, protein, microenvironmental levels, and dysregulated oncogenic signaling pathways. In the era of precision medicine, targeting oncogenic pathways to design drugs and to optimize treatment regimens for the lymphoma patients is feasible and clinically significant. As such, further understanding of the biology and the mechanisms behind lymphoma development and identification of oncogenic pathway activation and pathway-based biomarkers to better design precise therapies are challenging but hopeful. Furthermore, pathway-based targeted therapies in combination with traditional chemotherapy, single specific targeted antibody therapy, and immunotherapy might raise the hope for the patients with lymphoma, especially for relapsed and refractory lymphoma patients.

FIG. 1

Illustration of cross-communication network of BCR, PI3K, and NF-κB signaling pathways that harbor effective therapeutic targets in lymphoma. BCR signaling, PI3K/AKT/mTOR signaling, and NF-κB signaling are independent but interconnected and may form complex crosstalk network. One pathway may act as upstream or downstream of other pathways and some molecular targets function as key points and players involved in several pathways. These key molecules have been shown promise to be a good therapeutic target for effective treatment in lymphoid malignancies. (A) Tonic BCR signaling pathway and PI3K/AKT/mTOR signaling pathway; (B) chronic active BCR signaling; (C) canonical NF-κB signaling pathway; (D) noncanonical NF-κB signaling pathway. The arrows indicate direction of activating signaling steps; the light-colored bars indicate inhibitory signaling steps; the black bars show inhibition from therapeutic agents toward targets. BAFF-R, B-cell activating factor receptor; BCR, B-cell receptor; BTK, Bruton’s tyrosine kinase; CARD11, caspase recruitment domain family, member 11; IKK, IκB kinase; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; NEMO, NF-κB essential modifier; NIK, NF-κB-inducing kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3 kinase; TCR, T-cell receptor; TLRs, Toll-like receptors; TNFR, tumor necrosis factor receptor.

FIG. 2

Illustration of JAK/STAT signaling pathway that inspires effective therapeutic targets in lymphoma. JAK/STAT pathway is a key mediator of cytokine signaling in both physiological and pathological conditions. Upon binding cytokines, basally inactive JAKs engaged to cytokine receptors are phosphorylated and thereby phosphorylate STATs. After being dimerization, phosphorylated STATs translocate from cytoplasm to nucleus and then bind to specific targeted genes. In turn, this pathway is negatively regulated by SOCS and CIS. The inhibitors targeting JAKs, STATs, or ILs are being expected to show expected treatment efficacy in some lymphomas. JAK, Janus kinase; STAT, signal transducer and activator of transcription; SHP, Src homology region 2 domain-containing phosphatase; SOCS, suppressor of cytokine signaling; CIS, cytokine-inducible SH2-containing protein; PI3K, phosphoinositide-3-kinase; AKT, v-akt murine thymoma viral oncogene homolog1; mTOR, mechanistic target of Rapamycin; ERK, extracellular signal-regulated kinase; CCND1, cyclin D1; VEGF, vascular endothelial growth factor.

FIG. 3

Overview of apoptosis signaling pathway that contains effective therapeutic targets in lymphoma. The naturally occurring apoptosis pathway functions through extrinsic and intrinsic signaling and is controlled by a series of highly conserve molecules. Interfering pathologic apoptosis pathway and restoring its normal function seem to have therapeutic potential in many types of cancer. Among these therapeutic targets, BCL2, MYC, and p53 might be the suitable target candidates. FasL, Fas ligand; TNF, tumor necrosis factor; TNFR1, tumor necrosis factor receptor 1; FADD, fas associated via death domain; TRADD, TNFRSF1A associated via death domain; BID, BH3 interacting domain death agonist; tBID, truncated BID; BAX, BCL2 associated X; BCL2, B-cell lymphoma 2; BAK, BCL2 antagonist/killer; Myc, v-Myc avian myelocytomatosis viral oncogene homolog; ARF, alternate open reading frame; MDM2, mouse double-minute 2 protein; ATR, Ataxia telangiectasia and Rads-related protein; ATM, ataxia telangiectasia mutated; chk2, checkpoint kinase 2.

FIG. 4

Overview of PD-1/PD-Ls signaling pathway that acts as effective therapeutic targets in lymphoma. Upon binding to its ligands PD-Ls, PD-1 delivers co-inhibitory signals, negatively regulating T-cell function to maintain immune balance. In the cases of tumor, overexpressed PD-Ls activate PD-1 signaling, leading to exhaustion of effector T cell after interaction of PD-1 and PD-Ls. Targeting PD-1 and/or PD-L1 are the current focus of immunotherapy and clinical management in several solid tumor and hematologic malignancies. APC, antigen presenting cell; PD-1, programmed death-1; PD-L, programmed death-ligand; MHCII, major histocompatibility complex, class II; TCR, T-cell receptor; SHP, Src homology region 2 domain-containing phosphatase; ZAP70, zeta chain of T cell receptor associated protein kinase 70; PI3K, phosphoinositide-3-kinase; AKT, v-akt murine thymoma viral oncogene homolog1; ERK, extracellular signal-regulated kinase; FOXO-1, forkhead box 1; mTOR, mechanistic target of Rapamycin; NFAT, nuclear factor of activated T cells; NF-kB, nuclear factor-kappa B.